title: Egr1 regulates lithium-induced transcription of the Period 2 (PER2) gene.
abstract: A growing body of evidence suggests that the circadian molecular system is involved in the pathogenic and therapeutic mechanisms underlying bipolar disorders. Lithium, a representative mood stabilizer, has been reported to induce the Period 2 (PER2) gene; however, the underlying molecular mechanisms require further study. We found that lithium upregulated PER2 expression at the transcriptional level in neuronally differentiated SH-SY5Y human neuroblastoma cells. Promoter reporter analyses using serial deletions of the PER2 promoter revealed that two early growth response 1 (Egr1)-binding sites (EBS) between positions -180 and -100 are required for maximal activation of the PER2 promoter by lithium. Ectopic expression of Egr1 enhanced lithium-induced PER2 promoter activity, while a point mutation in EBS abolished it. Electrophoretic mobility shift assays and chromatin immunoprecipitation indicated that Egr1 bound directly to the PER2 promoter. Stimulation of the extracellular-signal regulated kinase (ERK)1/2/Elk1 pathway by lithium was functionally linked to PER2 expression through Egr1 induction, and lithium-induced PER2 expression was strongly attenuated by depletion of Egr1 by siRNA. Lithium also upregulated the expression of Per2 and Egr1 in mouse frontal cortex. Induction of Per2 by lithium was attenuated in Egr1(-/-) mice. In conclusion, lithium stimulates PER2 transcription through the ERK/Elk1/Egr1 pathway in neuronal cells, indicating a connection between the ERK-Egr1 pathway and a circadian gene system in the mechanism of action of lithium.
authors.affiliation: Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, Seoul 110-744, Republic of Korea.
authors.forename: Se Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Yu
authors.forename: Hong Guen
authors.initials: HG
authors.lastname: Park
authors.forename: Yong Min
authors.initials: YM
authors.lastname: Ahn
authors.forename: Yong Sik
authors.initials: YS
authors.lastname: Kim
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Kyooseob
authors.initials: K
authors.lastname: Ha
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D056950:Period Circadian Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C494113:Elk1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050807:ets-Domain Protein Elk-1; D008094:Lithium; D008156:Luciferases; D048052:Mitogen-Activated Protein Kinase 3
keywords: Bipolar disorder; Circadian gene; Egr1; Lithium; Mood stabilizer; Per2